The cytokines which utilize receptors containing the common gamma chain (gammac) are required at proscribed steps of T cell development and during the immune response. One of these, IL-15, is important for CD8 T cell, NK, NK-T, and intestinal intraepithelial lymphocyte development. However, the precise role of lL-15 in CD8 T cell development and function is not known. Mice lacking expression of IL-15 or lL-l5Ra lack memory phenotype CD8 T cells, but our preliminary data shows that CD8 memory T cells can be generated in these mice. This result questions the origin of memory-phenotype cells in normal mice and provides a strong rationale for the in-depth studies proposed here to determine the role of IL-15 in CD8 T cell development and immune response. The specific aims of the application are: Aim 1. To determine the requirements for IL-15 in CD8 T cell development. Studies will examine thymocyte subsets during fetal, neonatal and adult life to determine whether a defect in CD8 T cell development can be identified. Experiments will then focus on identifying the source of IL-15, hematopoietic or non-hematopoietic, needed for normal CD8 T cell production. Studies will examine whether CD8 T cell production/survival requires IL-15 expressed in the thymus versus the peripheral tissues. Aim 2. To determine the role of IL-15 in control of CD8 T cell immune responses. Our preliminary results show that virus infection of IL-1 5-/-IL-15Ralpha-/- mice generates CD44high memory CD8 T cells. Yet, uninfected IL-15-/-/IL- 5Ra-/- mice lack the CD44high CD8 T cell subset. We hypothesize that the strength of the initial activation signal regulates the level of IL-15 dependence of the immune response, and this theory will be tested by using a variety of immunization regimens and by examining whether CD4 T cell activation is IL-15 dependent. Model systems will also be used to determine the relevant source of IL-15 in controlling the magnitude of the response. Aim 3. To determine the role of IL-15 in generation and survival of CD8 memory T cells. Experiments in this aim will test whether antiviral memory CD8 T cells or memory-phenotype CD8 T cells from uninfected mice are IL-15-dependent once generated. Studies measuring turnover and survival in the presence or absence of IL-i5 will be performed. In addition, the expression pattern of IL-15R components during an immune response will be assessed. Transgenic mice expressing inducible IL-15Ralpha will be generated in order to distinguish between thymic and peripheral effects of IL-15Ralpha on CD8 T cell biology. These studies will provide a comprehensive analysis of the role of lL-15 in regulation of CD8 T cells.